Extensively drug-resistant tuberculosis (XDR TB) has emerged as a significant global epidemic and poses a particular threat to HIV-infected persons. Drug-resistant TB disease is predominantly thought to develop as a result of selection pressure for drug-resistant mutant bacilli (amplified resistance). Drug-resistant TB disease may also occur, however, from exposure to and infection with a TB strain which is already drug-resistant (primary transmission). Transmission of drug-resistant TB strains has been well-described in congregate settings, such as hospitals containing highly immunocompromised patients, but few studies have evaluated population-level transmission of drug-resistant TB, and none have done so in a high HIV prevalence setting. The collision of XDR TB and HIV in South Africa offers a unique, early opportunity to study these dual epidemics, which are anticipated to converge in other countries in the future. The current global crisis of drug-resistant TB is due to both amplified resistance and primary transmission, although the relative contribution of each is unknown. In Aim 1 of this application, we propose a prospective, population-based, cross-sectional study to determine the proportion of new XDR TB cases which develop due to primary transmission as opposed to amplified resistance in Tugela Ferry district, a rural area of South Africa with exceedingly high rates of XDR TB and HIV co-infection. We hypothesize that over three-quarters of XDR TB cases arise due to primary transmission. In Aim 2, we will combine molecular genotyping with contact tracing and social network analysis to provide insights into the relationships between XDR TB subjects with matching strain genotypes (clusters) and the locations where TB transmission may be occurring. We expect to identify that transmission is occurring in not only healthcare, but also community congregate settings. The findings from this study will lead to a better understanding of XDR TB transmission patterns in the Tugela Ferry community, which is critical for targeting interventions to curb the ongoing XDR TB epidemic. The proposed study will be the first to integrate epidemiologic, molecular, and social network analytic methods to study TB transmission in a high HIV prevalence setting. The interactions between HIV infection and drug-resistant TB have been identified as a priority research area by the NIH and the Federal TB Task Force, specifically epidemiologic research and greater use of genotyping to improve understanding of HIV and drug-resistant TB, and implementation of intensive contact tracing and outbreak investigation. This application will address these issues directly and take place at the epicenter of the convergent epidemics of TB, HIV, and drug-resistant TB in rural South Africa, where our research group has been working since 2002. Continuous, population-level surveillance for XDR TB, including culture and drug-susceptibility testing for all TB suspects in Tugela Ferry district, creates a unique opportunity to study XDR TB transmission.